Over 30% of estrogen receptor positive (ER+) tumors are not prevented by tamoxifen prophylaxis. The degree to which the interaction between levels of tamoxifen and estrogen levels in the breast contribute to the lack of response has not been determined. The effects of tamoxifen and aromatase inhibitors on estrogen-induced proteins cathepsin D and trefoil family factor-1 (TFF1) will be determined in breast ductal lavage fluid (DLF). The effects of the treatments will be determined after 6 months in women who are at high risk for breast cancer and in women with breast cancer who will begin tamoxifen treatment for adjuvant therapy. Since tamoxifen increases blood levels of estradiol, it is hypothesized that the effectiveness of tamoxifen may be compromised in some women because of competition for tamoxifen by estradiol in the breast or because of rapid clearance of tamoxifen or both. The levels of tamoxifen and estradiol will be measured in ductal lavage fluid (DLF) to ascertain the relationship between the ratio of these competitors and the estrogen-inducible proteins. Serum and salivary levels of tamoxifen will also be measured to determine their relationship to DLF levels of tamoxifen. Enzyme immunoassays will be developed in the Immunoassay Core Facility for tamoxifen and TFF1 as part of this project. The effects of aromatase inhibitors will also be evaluated in women who have been diagnosed with breast cancer. The estrogeninducible proteins will be assayed as a measure of the estrogen response. The possibility of hypersensitivity to estradiol caused by estrogen deprivation will be evaluated by relationship between the concentrations of estradiol and the estrogen-inducible proteins in DLF. The possibility of estrogenic activities of products of DHEA such as androst-5-ene-3beta,17beta-diol and 5alpha-androstane-3beta,17beta-diol during aromatase inhibitor treatment will also be evaluated. The proposed study takes advantage of our experience with ductal lavage and the assay of estradiol, cathepsin D, and androgens in DLF and the experience of the laboratory in developing new immunoassays. This limited study will provide sufficient information to determine the feasibility and potential value of a more thorough investigation. Treatment of women for prevention of breast cancer will be improved as a result of a better understanding of the pharmacology of drugs that antagonize or deplete estradiol.